Causative Antigen

• Celiac disease (CD) caused by immunologic non-IgE- mediated reaction to gliadin component of dietary glutens found in wheat, barley, and rye.
• Controversial whether oats also cause disease (lack of oat tolerance in CD may be due to contamination of oat grains with other grains)
  • The majority of patients with CD can consume a moderate amount of pure oats (up to 70 g per day in adults and 25 g per day in children) without side effects

Clinical Features

Disease Patterns	Features
Classic	Symptoms of malabsorption (steatorrhea, weight loss, or other signs of nutrient or vitamin deficiency) Presence of characteristic histologic small intestinal biopsy changes (including villous atrophy) Resolution of the mucosal lesions and symptoms with elimination of gluten-containing foods, usually within a few weeks to months.
Atypical	Extraintestinal symptoms predominant, with few/no GI symptoms noted by patient Diagnosis requires serologic testing, biopsy evidence of villous atrophy, and improvement of symptoms on a gluten-free diet.
Subclinical/silent-----------	No clinical symptoms, but have a positive serologic tests and biopsy evidence of villous atrophy (usually detected by screening of high-risk groups) After treatment with a gluten-free diet, many of these patients retrospectively recognize symptoms that they had not previously considered to be abnormal.
Potential	Patients with negative intestinal biopsies but have characteristic immunologic abnormalities (positive serology or increased intraepithelial lymphocytes). These patients often have a genetic predisposition, especially HLA-DQ2, and a first-degree relative with CD.
Latent	2 variants have been identified: Latent CD after disese resolves or is outgrown: disease present in past (usually in childhood), resolved completely with a gluten-free diet, and disease did not recur when a normal gluten-containing diet is resumed later in life. Latent CD before disease develops: normal mucosa was found at an earlier occasion while on a gluten-containing diet, but CD developed later in life.
Refractory	Patients with true disease (ie, not a misdiagnosis) who do not or no longer respond to a gluten-free diet. Some of these patients develop complications such as ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.
Gluten sensitivity (controversial)	Clinical response to a gluten-free diet in the absence of serologic/histologic findings

• Epidemiology
  • Biphasic incidence: 6-24 months old with first introduction of gluten into diet then 10-40 years old.
  • Prevalence increases with age and up to 15% of newly diagnosed are >65 years old
  • Occurs primarily in whites of Northern European ancestry (rare in Chinese, Japanese, subsaharan African)
  • High risk groups:
    • 99% with CD have HLA DQ2 and/or DQ8 (vs. 40% of the general population) thus CD is highly unlikely in patients without these haplotypes
    • Down syndrome
    • 1st and 2nd degree relatives of patients with celiac disease
    • Type 1 diabetes mellitus
    • IgA deficiency
    • Turner syndrome
    • Williams syndrome
    • Autoimmune thyroiditis
• Signs/symptoms:
  • GI:
    • Young child: chronic diarrhea, anorexia, abdominal distension/pain, weight loss, failure to thrive, malnutrition; some have vomiting
    • Older child/adult: as above, constipation or diarrhea (bulky, foul-smelling), stools may float due to steatorrhea, flatulence, distension
    • Secondary lactose intolerance
    • "Celiac crisis" - rare life-threatening syndrome, mostly in children, characterized by severe diarrhea, hypoproteinemia, metabolic/electrolyte imbalances
  • Skin:
    • Dermatitis herpetiformis (DH)
      • Up to 24% of adults with celiac have DH, 85% with DH have intestinal biopsy changes
      • Pruritic and burning papular vesicular eruption usually located symmetrically on the extensor surfaces of the elbows, knees, buttocks, sacrum, face, neck, trunk, and occasionally within the mouth
    • Apthous stomatitis
    • Chronic urticaria - case reports of urticaria in children and adults with CD that resolve on gluten-free diet
    • Other associated skin findings: acquired icthyosis, cutaneous amyloid, cutaneous vasculitis, eczema, epidermal necrolysis, nodular prurigo, pityriasis rubra pilara, pustular dermatitis
  • Autoimmune disease - associated with development of type 1 DM, autoimmune thyroid disease, connective tissue disease
  • Growth and development:
    • Failure to thrive
    • Short stature
    • Delayed puberty
  • Neuropsychiatric disease - neurologic or behavioral symptoms may be primary/initial symptom
    • Hypotonia
    • Cerebellar ataxia
    • Developmental delay, learning disorders and ADHD
    • Headache
    • Mood changes, depression, anxiety
    • Carpal tunnel
    • Epilepsy with occipital calcifications
    • Myopathy
  • Dental enamel defects
  • Metabolic bone disease - osteomalacia/osteoporosis due to vitamin D and calcium malabsorption
  • Arthritis
  • Liver disease - mild elevation of AST, ALT (with case reports of severe liver disease)
  • Iron deficiency (with or without) anemia - not responsive to iron replacement
  • Hyposplenism - etiology unknown
  • Kidney disease - glomerular IgA deposition in up to a third, most without adverse consequences
  • Idiopathic pulmonary hemosiderosis
    • Lane-Hamilton syndrome - coexistence of CD with pulmonary hemosiderosis, both improving with gluten-free diet
  • Reproductive/Gynecologic
    • Females with increased frequency of later menarche, earlier menopause, secondary amenorrhea, recurrent miscarriage, and infertility
    • Males with abnormal sperm, androgen resistance
  • Myocarditis, cardiomyopathy
  • Atrophic glossitis
  • Pancreatitis
  • Malignancy - increased risk of lymphomas and GI cancers in adults
  • Mortality - increased vs. general population likely due to malignancy, possibly decreased with adherence to gluten-free diet

Note:

• CD presents as a clinical spectrum from subclinical/silent to classical disease
• In children with subtle symptoms and CD detected by screening, the most common symptoms included: Iron deficiency with/without anemia, recurrent abdominal pain, mood changes, recurrent aphthous stomatitis, poor appetite, recurrent diarrhea, short stature, abdominal distention, constipation, pubertal delay, hypoalbuminemia
  
  

Diagnosis

Indications for Testing

• Individuals without other explanations for signs/symptoms above
• Chronic GI symptoms including diarrhea, malabsorption, failure to thrive, constipation, abdominal pain, distension, or vomiting (includes patients with symptoms suggestive for IBS or lactose intolerance which frequently coexist with CD)
• All members of high-risk groups (particularly if symptomatic): 1st degree relatives of patients with CD, autoimmune thyroiditis, type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency.
  • Controversial to test asymptomatic children in high risk groups. If screening done, perform when patient at least 3 years old and on a gluten-containing diet for at least 1 year. If initial results are negative, screening tests should be repeated at regular intervals (eg. 3-5 years), or when symptoms develop.

Lab Testing

Useful Tests
Serum IgA level	IgA deficiency found in 2% with CD Deficiency may result in false negative celiac disease IgA antibody testing
Anti-tTG (tissue transglutaminase) IgA	Recommended as first-level screening test Best cost-effective single test with good sensitivity/specificity May be false positive in setting of other autoimmune diseases, including type 1 diabetes Sensitivity/specificity >95%
Anti-tTG IgG	Obtain instead of Anti-tTG IgA in patient with IgA deficiency Widely variable sensitivity (12.6-99.3%) and specificity (86.3-100%)
Anti-endomysial antibody (EMA) IgA	Expensive, time consuming, and accuracy varies by lab expertise but may be useful in patients with uncertain diagnosis Should only be used as a confirmatory test in the case of equivocal or possibly false positive anti-tTG Sensitivity >90% and specificity >98% False negative in IgA deficiency
DGP (Deamidated Gliadin Peptide) IgG	Second generation antigliadin antibody test that yields diagnostic accuracy similar to tTG IgA Sensitivity/specificity >90%
HLA typing for DQ2 and DQ8	May be useful in individuals with equivocal intestinal biopsy findings since CD is very unlikely if neither HLA type is present
Less Useful Tests
Antigliadin IgA	Sensitivity >52%, specificity >72% False negative in IgA deficiency
Antigliadin IgG	Sensitivity >83%, specificity >47%
Antireticulin IgA	Found in 60% of CD and 25% of DH but not in other autoimmune diseases Anti-reticulin IgG found in other diseases (bullous dermatoses) and sometimes normal patients No longer commonly used

Note:

• Combination of anti-tTG and DGP antibody levels may be best combination of tests for serologic diagnosis of CD
• All testing should be performed on a gluten-rich diet (at least 1-3 months before test obtained)
  • Antibody levels remain elevated for 1-12 months after gluten removed from diet therefore it may be reasonable to obtain serology in patients who have only recently begun a gluten-free diet.
• Serologic testing may not be as accurate in children <5 years and is less accurate <2 years old

Biopsy

• Note that European guidelines (2012) suggest that a biopsy of the small intestine may not be required in children with typical symptoms, a high titer of anti–tTG antibodies (>10 times the upper limit of normal), and predisposing HLA genotypes

Small Intestine

• Patients with positive serologic testing should have an intestinal biopsy to establish the diagnosis
• Biopsy should be performed while on a gluten-containing diet.
• Multiple biopsies should be taken from the distal duodenum and duodenal bulb and interpreted by an expert pathologist; the disease may have a patchy distribution.
• Histologic findings in CD range from increased intraepithelial lymphocytes to a flat mucosa with total mucosal atrophy, complete loss of villi, enhanced epithelial apoptosis, and crypt hyperplasia
• Severity of abnormality does not necessarily correlate with clinical symptoms
• If serology positive but biopsy negative, consider repeating biopsy after 6-12 weeks on high gluten diet

Skin (Dermatitis Herpetiformis)

• DH diagnosis confirmed by the demonstration of granular IgA deposition in an area of the skin not affected by blistering, along the subepidermal membrane.
• Biopsy alone is sufficient to make the diagnosis of DH. Anti-tTG antibodies are elevated in patients with DH.
• Many experts recommend treatment based on the results of the skin biopsy alone, and an intestinal biopsy is not required.

Algorithm

Fasano (2012)

Treatment

Indications for Treatment
Treat	Positive intestinal biopsy and CD symptoms (including nonspecific symptoms such as constipation or abdominal pain). Positive intestinal biopsy and belonging to high-risk group (eg, relatives of patients with established celiac disease, or patients with type 1 diabetes), whether or not there are associated clinical symptoms. Dermatitis herpetiformis confirmed by skin biopsy.
Don't treat	Negative intestinal biopsy (ideally expert review of multiple biopsies), positive serology, no symptoms Monitor clinically and biopsy if symptoms develop
Maybe treat (controversial)	Negative intestinal biopsy, positive serology, with symptoms of CD - most with this profile might eventually develop intestinal biopsy changes

• Life-long gluten-free diet
  • Strict elimination of wheat, rye, barley.
  • Oat elimination controversial - consider limiting to 50-60 g/day in mild disease and strict elimination in severe disease

• "CELIAC"
  • Consultation with dietitian
  • Education
  • Lifelong gluten-free diet
  • Identification and treatment of nutritional deficiencies: iron, calcium, phosphorus, folate, B12, and fat-soluble vitamins.
  • Access to an advocacy group
  • Continuous long-term follow-up by a multidisciplinary team
• Secondary lactose intolerance - avoidance of lactose until small intestine normalizes with gluten-free diet
• Dermatitis herpetiformis - gluten free diet results in improvement in 6-12 months therefore dapsone usually started (improves skin but not intestinal disease)
• Hyposplenism - pneumoccocal vaccination
• Bone health - consider DEXA scan in adults, treatment of osteoporosis
• Consider screening 1st degree family members for CD (particularly siblings)

Monitoring

• 70% with clinical improvement 2 weeks after starting diet
• Obtain pre-diet tTG IgA (or IgA antigliadin) level and monitor decline over time - should fall to baseline level 3-12 months later depending on pre-treatment level (eg check level pre-diet and at 6 months). If patient remains well, check level annually to monitor adherence and also obtain level if symptoms recur.
  • tTG IgA half-life is 6-8 weeks
  • If the levels do not fall, the patient is usually continuing to ingest gluten intentionally or inadvertently
  • Use same laboratory for testing. Minor fluctuations in IgA antigliadin or IgA tTG levels are the norm and should not be overinterpreted.
  • IgG antigliadin level also falls after diet but is slower to fall than antigliadin IgA
• Repeat Biopsy
  • Normal serology does not reliably indicate recovery from villous atrophy
  • Biopsy not indicated for patients with the following profile: initially presented with CD symptoms, positive antibodies, and positive intestinal biopsy (villous atrophy) followed by resolution of symptoms and marked decrease in antibodies on a gluten-free diet.
  • For other cases, consider repeat biopsy 9-12 months after starting gluten free diet
• Gluten rechallenge (4 slices of bread for 4-6 weeks) - generally not required unless diagnosis remains in question. A rare complication of challenge is "gliadin shock" with fulminant diarrhea requiring treatment with steroids.

References